Subversion of dendritic cell immunity to Cryptococcus gattii by a novel phagosomal F-actin cage structure
Date
2020-04-28
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Abstract
The highly virulent fungus, Cryptococcus gattii, emerged as a novel respiratory pathogen on Vancouver Island (British Columbia, Canada) nearly two decades ago and has spread to the surrounding regions encompassing the Pacific Northwest of United States, where there is an ongoing outbreak. C. gattii is a major cause of life-threatening cryptococcosis in immunocompetent individuals and has a mortality rate of up to 33%. Host immune response is a key determining factor for the development of cryptococcal disease. It is now recognized that evasion of host immune recognition is a hallmark of C. gattii pathogenesis, but the mechanism of immune evasion remains unclear. There is increasing evidence that C. gattii subverts dendritic cell (DC) activation to evade the protective T helper cell-mediated immunity. This thesis demonstrates that primary human DC can phagocytose C. gattii yeasts but trafficking to the late phagolysosome is blocked by retention of a filamentous actin (F-actin) cage on the phagosomes. Structural studies by super resolution microscopy revealed a novel, highly branched F-actin cage that physically interfered with lysosomal fusion. C. gattii F-actin cage promoted immune evasion by silencing the canonical RelA signaling of the NF-κB pathway required for DC costimulation and T cell activation. Disruption of the F- actin cage through targeted inhibition or by TNF-α signaling reprogrammed quiescent DC to immunocompetent antigen-presenting cells (APCs). Furthermore, the presence of phagosomal F-actin cage corresponded with the presence of C. gattii polysaccharide capsule. Acapsular mutant strains did not retain phagosomal F-actin and were remarkable at inducing DC activation and T cell proliferation. Collectively, our results have uncovered a unique mechanism of DC immune subversion by intracellular pathogens such as hypervirulent C. gattii. Manipulations of this mechanism can potentially inform novel therapeutic interventions against C. gattii.
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Keywords
Dendritic cell, Cryptococcus, Fungus, Immune evasion
Citation
Jamil, K. (2020). Subversion of dendritic cell immunity to Cryptococcus gattii by a novel phagosomal F-actin cage structure (Master's thesis, University of Calgary, Calgary, Canada). Retrieved from https://prism.ucalgary.ca.